(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid of the Formula (I) (rosuvastatin) is a compound known according the state of the art, which has been described for the first time in European Patent No. 521471 together with certain pharmaceutically acceptable salts including the ammonium salt and calcium salt of the Formula (IV)

Published International Patent Application WO01060804 discloses crystalline ammonium, methylammonium, ethylammonium, diethanolammonium, tris-(hydroxymethyl)-methylammonium, benzylammonium and 4-methoxybenzyl-ammonium salts of rosuvastatin. The method disclosed in said application for the preparation of the methylammonium salt comprises reacting rosuvastatin of the Formula (I) with methylamine in methanol, filtering and washing the filtered salt with acetonitrile. Other ammonium salts were prepared by acidifying the methylammonium salt in aqueous acetonitrile or water-ethylacetate biphasic solvent system and reacting rosuvastatin acid thus obtained with the corresponding amine.
The subject of Published International Patent Application WO2005051921 is a multi-step method for purifying rosuvastatin calcium salt of the Formula (IV) using rosuvastatin isopropylammonium or cyclohexylammonium salts. Rosuvastatin calcium salt of the Formula (IV) is acidified in aqueous acetonitrile solvent and rosuvastatin of the Formula (I) thus obtained is extracted with ethylacetate. Thereafter rosuvastatin is transformed into isopropylammonium or cyclohexylammonium salt in acetonitrile or ethylacetate. Said ammonium salts are converted into the sodium salt in an aqueous solution, which is transformed into rosuvastatin calcium salt using methods known in the state of the art.
Published International Patent Application WO2005077916 discloses rosuvastatin ammonium salts in general wherein the cation is different from ammonium, methylammonium, ethylammonium, diethanolammonium, (tris-hydroxymethyl)-methylammonium, benzylammonium or 4-methoxy-benzylammonium. Crystalline and amorphous rosuvastatin cyclohexyl-, dicyclohexyl-, isopropyl-, diisopropyl- and (S)-1-methylbenzylammonium salts are disclosed. The ammonium salts are prepared starting from rosuvastatin of the Formula (I) in ethylacetate solvent.
In Published International Patent Application WO 2006136407, a method for the preparation of rosuvastatin calcium salt of the Formula (IV) in amorphous form has been disclosed, which uses a rosuvastatin salt of the Formula (II) formed with an organic ammonium cation
as starting material. The application discloses and claims several rosuvastatin ammonium salts, such as pyrrollidinium, piperidinium, morpholinium, adamantylammonium, N,N-dicyclohexylammonium, N-methyl-cyclohexylammonium, tert-octylammonium salts. The ammonium salts are prepared starting from a rosuvastatin ester or from rosuvastatin lactone of the Formula (VII)
by reacting said compound with the corresponding amine in aqueous solution or in the mixture of water and tetrahydrofurane. Preparation of several organic ammonium salts including rosuvastatin tert-butylammonium (TBA) salt of the Formula (IIa)
have been disclosed in the examples. However, no physical-chemical or analytical data for rosuvastatin TBA salt have been disclosed. According to the methods disclosed in the above-mentioned application, rosuvastatin TBA salt of the Formula (IIa) has not been used directly as a starting material for the preparation of rosuvastatin calcium salt of the Formula (IV).
Published International Patent Application WO 2007125547 discloses a “one-pot” method for the preparation of rosuvastatin of the Formula (I) or rosuvastatin ammonium salts of the Formula (II). Ammonium salts are prepared by subjecting rosuvastatin ketal tert-butylester of the Formula (VIII)
to acidic and subsequently alkaline hydrolysis, transforming the thus obtained rosuvastatin sodium salt of the Formula (VI)
into rosuvastatin of the Formula (I) and reacting rosuvastatin with the corresponding amine. Ammonium salt formation is carried out in acetonitrile.
Published International Patent Application WO2007000121 discloses a method for the preparation of rosuvastatin calcium salt of the Formula (IV) in amorphous or crystalline form starting—among others—from an amide of rosuvastatin formed with a primary amine. Rosuvastatin methylamide corresponding to the general Formula (III)
wherein R4 is methyl, R5 is hydrogen, is hydrolysed for 17 hours with an inorganic base—lithium hydroxide—in aqueous tetrahydrofurane solution at the temperature of 60° C.
In Published International Patent Application WO 2007125547, alkaline hydrolysis of rosuvastatin amides formed with secondary amines has been described using an alkali metal hydroxide, preferably sodium hydroxide. Among the amides of rosuvastatin, diisopropylamide is referred to specifically. The alkali metal salt obtained is transformed into rosuvastatin of the Formula (I) by acidification and subsequently converted into the corresponding ammonium salt using organic bases. Finally the ammonium salt is transformed into the sodium salt of the Formula (VI), which is finally converted into the calcium salt of the Formula (IV). The application furthermore discloses a crystalline form of rosuvastatin TBA salt of the Formula (IIa), which is characterized by an X-ray diffractogram. However, the disclosed purification method is complicated to carry out, several organic solvents are required for the extraction and during the crystallization of the TBA salt, it is necessary that the organic solvent be introduced in portions and it is required that after each addition except the final one, the solvent be removed by evaporation.
Published International Patent Application WO 2008044243 is related to a one-pot method for the preparation of rosuvastatin calcium salt of the Formula (IV), which comprises alkaline hydrolysis of rosuvastatin n-butylamide or rosuvastatin diizopropylamide by boiling with aqueous sodium hydroxide in ethyleneglycol. The alkali metal salt thus obtained is treated with an acid in water-ethylacetate solvent system and rosuvastatin of the Formula (I) thus obtained is converted into an organic ammonium salt by reacting with the corresponding organic base. Ammonium salt of rosuvastatin is thereafter converted into the sodium salt, which is transformed into rosuvastatin calcium salt of the Formula (IV).
Published International Patent Application WO 2005123082 is related to a combined pharmaceutical preparation consisting of rosuvastatin and acipimox. Among many other salt forms of rosuvastatin, rosuvastatin zinc salt is mentioned. However neither physical-chemical parameters of rosuvastatin zinc salt, nor a method of preparation thereof, or the stoichiometry of the salt have been disclosed.
Rosuvastatin zinc (2:1) salt of the Formula (V)
as well as methods for preparation thereof and physical-chemical properties of the same have been disclosed for the first time in Published International Patent Application WO 2007119085.
Published International Patent Application WO 2008015563 is related to the preparation of rosuvastatin zinc (2:1) salt of the Formula (V) starting from rosuvastatin tert-butylester of the Formula (IX)
as well as from rosuvastatin tert-butylammonium salt by transforming either starting material first into rosuvastatin sodium salt of the Formula (VI).
Published International Patent Application WO 2009047577 is related to a method for the preparation of rosuvastatin zinc salt of the Formula (V), wherein rosuvastatin of the Formula (I), sodium salt or an alkylester thereof, rosuvastatin lactone of the Formula (VII) or rosuvastatin ketal tert-butylester have been used as starting materials.
In published International Patent Application WO 2010082072, methods are disclosed for converting rosuvastatin TBA salt of the Formula (IIa) into rosuvastatin calcium salt of the Formula (IV) or rosuvastatin zinc salt of the Formula (V) using ethylacetate-water solvent system.
It is well known according to the state of the art that compounds belonging to the group of statins are easily transformed into their lactone form already at room temperature. Among others, published International Patent Application WO 2005077916 discloses the transformation of rosuvastatin diisopropylammonium salt into rosuvastatin lactone at pH 3 at the boiling temperature of toluene in six hours. Under such conditions, rosuvastatin ammonium salts (and analogously the calcium salt) undergo transformation into rosuvastatin of the Formula (I) in the first step, which is subsequently converted into rosuvastatin lactone of the Formula (VII) with full conversion. The observation that the lactonization takes place even at room temperature in an organic solvent with significant reaction rate is supported by experimental data. It has been found that the concentration of the lactone impurity rapidly exceeds the limit value prescribed by ICH Guidelines. Furthermore, it has been established by experimental evidence that the rate of lactonization is several times higher in acidic aqueous medium than in an organic solvent.
In most of the methods discussed above, rosuvastatin ammonium salts of the general Formula (II) are produced from rosuvastatin of the Formula (I) obtained in acidic media. The common disadvantages of these methods resides in that besides the extra step in the technology, the rate of lactonization in an acidic media is high which results in the decrease of yield and the contamination of the product.
During the transformation of rosuvastatin ammonium salts into rosuvastatin calcium salt of the Formula (IV) or rosuvastatin zinc salt of the Formula (V) according to the methods discussed above, the concentration of the lactone impurity usually remains unchanged, therefore the lactone impurity present in an intermediate of the general Formula (II) will appear in the drug substance as well as in the finished drug product.
In the methods according to the state of the art starting from a rosuvastatin amide of the general Formula (III), the hydrolysis of the amide is carried out in the presence of an alkali metal- or an alkali earth metal hydroxide and the reaction is carried out in an organic solvent. In this way, during the first step, a rosuvastatin salt with the specific alkali metal or alkali earth metal is formed, which requires further purification. However, since there are no suitable methods known in the state of the art for the purification of an alkali metal or alkali earth metal salt of rosuvastatin, the purification can be advantageously carried out by transforming the alkali metal or alkali earth metal salt of rosuvastatin into an ammonium salt of the same and purifying the ammonium salt by crystallization. Reacting the purified ammonium salt with an alkali metal hydroxide subsequently yields an alkali metal salt of rosuvastatin, preferably rosuvastatin sodium salt of the Formula (VI), which is transformed in the last step into rosuvastatin calcium salt by reacting with an inorganic calcium compound.
In conclusion, methods known according to the state of the art starting from a rosuvastatin amide of the general Formula (III) include extra steps in the technology, thus decreasing the efficiency and economy of the manufacturing process, the reagents and solvents are environmentally harmful and potential byproducts increase the contamination of the product. It can also be concluded that the purity of the final product is greatly influenced by the purity of the rosuvastatin ammonium salt of the general Formula (II) used in the manufacturing process.
The state of the art is silent about a method which is suitable for directly transforming a rosuvastatin amide of the general Formula (III) into a rosuvastatin ammonium salt of the general Formula (II), rosuvastatin calcium salt of the Formula (IV) or rosuvastatin zinc salt of the Formula (V), respectively.